External fixation pins are commonly used to stabilize orthopedic injuries and are considered to be fast and minimally invasive tools to allow for easy reduction of fractures. Despite the promising advantages with respect to damage control in orthopedics, pin tract infection and pin loosening are frequently occurring complications of external fixations.
Due to the contact with external skin layers, fixation pins may act as gateways for bacteria. Reported infection rates for external fixator fracture treatments range from 0.5% up to 50% and often cause bone loss, resulting in a decreased pin-bone interface. See Hutson J. J. et al., “Infections in Periarticular Fractures of the Lower Extermity Treated with Tensioned Wire Hybrid Fixators”J Orthop Trauma 12 214-218 (1998); Mahan j. et al. “Factors in Pin Tract Infections” Orthopedics 14 305-308 (1991); and Masse A. et al., “Prevention of Pin Track Infection in External Fixation with Silver Coated Pins: Clinical and Microbiological Results” J Biomed Mater Res 53 600-604 (2000). Conversely, instability of the pin-bone construct can lead to pin loosening and further infection. Thus, inhibiting bacterial adhesion may be seen as the most critical step in preventing implant associated infections. See Brunski J. B. et al., “Biomaterials and Biomechanics of Oral and Maxillofacial Implants: Current Status and Future Developments” Int J Oral Max Impl 15 15-46 (2000) and Hetrick E. M. et al., “Reducing Implant Related Infections: Active Release Strategies” Chem Soc Rev 35 780-789 (2006).
In order to overcome the poor accessibility of the bone-infected site by systematically administered antibiotics, many researchers have attempted to reduce infections at the bone-pin interface by designing functional surface coatings for local drug administration. See Brohede U. et al., “Multifunctional Implant Coatings Providing Possibilities For Fast Antibiotics Loading with Subsequent Slow Release”J Mater Sci Mater Med 20 1859-1867 (2009), the entirety of which is hereby incorporated by reference.
The major advantage of local antibiotics delivery compared to conventional systemic delivery for both infection prevention and treatment is that high local doses of antibiotics against specific pathogens associated with implant infection can be administered without reaching systemic toxicity levels of the drug itself. However, the effectiveness of antibiotics-loaded implant coatings is strongly dependent on the rate and manner in which the drug is released.
If the antibiotics are released at levels below the minimum inhibition concentration (MIC), bacterial resistance may be induced at the release sit. A six hour post implantation “decisive period” during which the prevention of bacterial adhesion is critical to the long-term success of the implant has been identified. See Poelstra K. A. et al., “Prophylactic Treatment of Gram-positive and Gram-negative Abdominal Implant Infections Using Locally Delivered Polyclonal Antibodies”J Biomed Mater Res 60 206-215 (2002). Thus, an optimum local antibiotic release profile for orthopedic implants should feature a high initial release rate during the first hours after implantation, followed by a sustained release to inhibit the occurrence of latent infection and allow for protective fibrous capsule formation as well as tissue integration. See Zilbermann M. et al., “Antibiotic-eluting Medical Devices for Various Applications” J Control Release 120 202-215 (2008) and Anderson J. H. “Biological Responses to Materials” Annu Rev Mater Res 31 81-110 (2001).
Bioactive ceramics and ceramic coatings have been investigated by several researchers as drug delivery vehicles for transport and sustained release of antibiotics. Hydroxyapatite (HA) is widely used in orthopedic surgery due to its excellent osteoconductive properties. Numerous techniques are known for coating implants with HA, including plasma spraying, dip coating, sputter deposition, electrophoretic deposition and sol-gel synthesis. The biomimetic method of HA coating requires soaking the implant in a simulated body fluid at an appropriate temperature and pH. Plasma sprayed HA coatings on implant surfaces have demonstrated a high clinical success rate based on greater bone-pin contact, enhanced bone-integration and long term fixation. Nevertheless, incorporating drugs into a plasma sprayed HA coating during deposition is not feasible due to the high process temperatures of the plasma flame.
Biomimetically deposited HA coatings offer a straight-forward approach to prepare implant coatings at low process temperature having good adhesion, as well as step coverage. Implant surfaces functionalized with a hydroxyapatite (HA) coating contribute towards an enhanced bone bonding capability and increases bone in-growth towards the implant surface. In addition, such HA coatings have shown promising potential to be used as a drug vehicle for local drug delivery at the implantation site. The nanoporous structure of such HA coatings allow loading antibiotics by a simple soaking procedure and it has been shown that it is possible to incorporate growth factors to promote tissue healing as well as to co-load growth-factors and antibiotics into the HA-matrix.
Even if biomimetic HA-coatings appear to be promising vehicles for local administration of antibiotics, the longest antibacterial effect demonstrated till date using this approach does not exceed three days. Chai F. et al., “Antibacterial Activation of Hydroxyapatite (HA) with Controlled Porosity by Different Antibiotics” Biomol Eng 24 510-514 (2007). Thus, a major challenge related to antibiotic-loaded HA coatings lies in increasing the action time of the antibiotics at the implant site.
Another well documented challenge is that native amorphous TiO2 has very poor ability to let HA form on its surface through biomimetic precipitation from a solution, whereas HA crystallizes spontaneously on the crystalline anatase and rutile phases of TiO2 when soaked in simulated body fluid.